Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 08 2021
01 08 2021
Historique:
received:
25
11
2020
revised:
25
01
2021
accepted:
05
03
2021
pubmed:
11
4
2021
medline:
2
4
2022
entrez:
10
4
2021
Statut:
ppublish
Résumé
To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer. We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures. We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (M The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
Identifiants
pubmed: 33837006
pii: 1078-0432.CCR-20-4574
doi: 10.1158/1078-0432.CCR-20-4574
pmc: PMC8338756
mid: NIHMS1683912
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4287-4300Subventions
Organisme : NIAID NIH HHS
ID : R01 AI081848
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA249175
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201189
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2021 American Association for Cancer Research.
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